WO2013039057A1 - ピロリジン－３－イル酢酸誘導体 - Google Patents

ピロリジン－３－イル酢酸誘導体 Download PDF

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Publication number
WO2013039057A1
WO2013039057A1 PCT/JP2012/073171 JP2012073171W WO2013039057A1 WO 2013039057 A1 WO2013039057 A1 WO 2013039057A1 JP 2012073171 W JP2012073171 W JP 2012073171W WO 2013039057 A1 WO2013039057 A1 WO 2013039057A1
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Prior art keywords
methyl
group
mmol
compound
carbamoyl
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PCT/JP2012/073171
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English (en)
French (fr)
Japanese (ja)
Inventor
吉田　一郎
忠志 岡部
泰信 松本
信久 渡辺
芳章 大橋
裕二 鬼澤
均 原田
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エーザイ・アール・アンド・ディー・マネジメント株式会社
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Priority to NZ620469A priority Critical patent/NZ620469B2/en
Priority to CA2844617A priority patent/CA2844617C/en
Application filed by エーザイ・アール・アンド・ディー・マネジメント株式会社 filed Critical エーザイ・アール・アンド・ディー・マネジメント株式会社
Priority to KR1020147003630A priority patent/KR101963922B1/ko
Priority to EP12831085.1A priority patent/EP2757103B1/en
Priority to MX2014002210A priority patent/MX358494B/es
Priority to DK12831085.1T priority patent/DK2757103T3/en
Priority to CN201280041634.0A priority patent/CN103764648B/zh
Priority to MEP-2016-37A priority patent/ME02383B/me
Priority to SG11201400163WA priority patent/SG11201400163WA/en
Priority to RU2014107536A priority patent/RU2615135C2/ru
Priority to RS20160106A priority patent/RS54582B1/en
Priority to JP2013533669A priority patent/JP5829689B2/ja
Priority to ES12831085.1T priority patent/ES2564732T3/es
Priority to SI201230463T priority patent/SI2757103T1/sl
Priority to PL12831085T priority patent/PL2757103T3/pl
Priority to AU2012309556A priority patent/AU2012309556B2/en
Priority to BR112014004267-5A priority patent/BR112014004267B1/pt
Priority to UAA201401661A priority patent/UA112873C2/uk
Publication of WO2013039057A1 publication Critical patent/WO2013039057A1/ja
Priority to IL230804A priority patent/IL230804A/en
Priority to ZA2014/00918A priority patent/ZA201400918B/en
Priority to HK14106800.1A priority patent/HK1193407A1/xx
Priority to HRP20160166TT priority patent/HRP20160166T1/hr
Priority to SM201600071T priority patent/SMT201600071B/xx

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/445—Non condensed piperidines, e.g. piperocaine
    • A61K31/4523—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems
    • A61K31/454—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems containing a five-membered ring with nitrogen as a ring hetero atom, e.g. pimozide, domperidone
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/04—Drugs for disorders of the alimentary tract or the digestive system for ulcers, gastritis or reflux esophagitis, e.g. antacids, inhibitors of acid secretion, mucosal protectants
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • A61P37/02—Immunomodulators
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D207/04—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
    • C07D207/10—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D207/16—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a chain containing hetero atoms as chain links

Definitions

  • the present invention relates to a pyrrolidin-3-ylacetic acid derivative. More particularly, the present invention relates to a pyrrolidin-3-ylacetic acid derivative that can be used as a therapeutic agent for inflammatory bowel disease.
  • Chemokines are the main cell migration factors in the body, and control tissue infiltration of lymphocytes through enhancement of cell movement and activation of cell adhesion molecules. Chemokines are classified into four subfamilies, CC, CXC, C, and CX3C, based on the sequence of their first two cysteine residues.
  • Fractalkine is the only member of the CX3C chemokine, and its structure and function have distinctive features not found in other chemokines.
  • fractalkine binding to the receptor CX3CR1 it is possible to mediate strong adhesion alone without the intervention of selectins and integrins even in the presence of a physiological blood flow rate. That is, the fractalkine-CX3CR1 cell invasion system mediates a function similar to the multistage cell invasion mechanism via selectins and integrins in a single step reaction.
  • Fractalkine is induced when vascular endothelial cells are treated with inflammatory cytokines TNF and IL-1.
  • CX3CR1 is expressed in a part of T cells in monocytes and NK cells, but is not expressed in neutrophils.
  • the fractalkine-CX3CR1 cell invasion system appears to be a very efficient mechanism for recruiting certain immune cells on or into the endothelial cells of damaged tissues.
  • Non-Patent Document 1 Regarding the relationship between the fractalkine-CX3CR1 system and pathological conditions, the fractalkine-CX3CR1 system is involved in the onset and pathology of autoimmune diseases such as rheumatoid arthritis, inflammatory bowel disease, lupus nephritis, and multiple sclerosis.
  • Non-Patent Document 2 Regarding inflammatory bowel disease in particular, it has been reported that the expression of fractalkine is enhanced at the inflammatory site of the large intestine tissue of the patient, and that CX3CR1 plays an important role in infiltration of immune cells into the intestinal tissue.
  • Non-Patent Document 2 Regarding the inflammatory bowel disease in particular, it has been reported that the expression of fractalkine is enhanced at the inflammatory site of the large intestine tissue of the patient, and that CX3CR1 plays an important role in infiltration of immune cells into the intestinal tissue.
  • Patent Document 7 is described as being useful as an antagonist of the chemokine CCR2 receptor, the target chemokine family is different.
  • the problem to be solved by the present invention is to provide a compound having an inhibitory action in the fractalkine-CX3CR1 pathway.
  • a compound represented by the formula (1) or a pharmacologically acceptable salt thereof [R is a C 1-6 alkyl group having 1 to 3 substituents which are unsubstituted or selected from substituent group A, and 1 to 3 substituents which are unsubstituted or selected from substituent group A means a C 3-8 cycloalkyl group or an unsubstituted or a substituent selected from the substituent group a to 1-3 Yes C 3-8 cycloalkenyl group, having, X represents a C 1-6 alkyl group, Y and Z are the same or different and each represents a halogen atom or a C 1-6 alkyl group having 1 to 3 substituents selected from unsubstituted or substituent group B; n means 0 or 1; Substituent group A consists of halogen atoms, Substituent group B consists of halogen
  • a medicament comprising the compound according to any one of [1] to [7] or a pharmaceutically acceptable salt thereof as an active ingredient.
  • a therapeutic agent for inflammatory bowel disease comprising the compound according to any one of [1] to [7] or a pharmacologically acceptable salt thereof as an active ingredient.
  • the therapeutic agent according to [9], wherein the inflammatory bowel disease is ulcerative colitis or Crohn's disease.
  • An inhibitor of the fractalkine-CX3CR1 pathway comprising as an active ingredient the compound according to any one of [1] to [7] or a pharmacologically acceptable salt thereof.
  • a fractalkine inhibitor comprising the compound according to any one of [1] to [7] or a pharmacologically acceptable salt thereof as an active ingredient.
  • a CX3CR1 inhibitor comprising the compound according to any one of [1] to [7] or a pharmacologically acceptable salt thereof as an active ingredient.
  • a method for treating inflammatory bowel disease comprising administering to the patient a compound according to any one of [1] to [7] or a pharmacologically acceptable salt thereof.
  • the method according to [14] wherein the inflammatory bowel disease is ulcerative colitis or Crohn's disease.
  • a method for inhibiting the fractalkine-CX3CR1 pathway comprising administering the compound of any one of [1] to [7] or a pharmacologically acceptable salt thereof to a patient.
  • a method for inhibiting fractalkine comprising administering the compound according to any one of [1] to [7] or a pharmaceutically acceptable salt thereof to a patient.
  • a method for inhibiting CX3CR1 comprising administering the compound of any one of [1] to [7] or a pharmaceutically acceptable salt thereof to a patient.
  • [24] Use of the compound according to any one of [1] to [7] or a pharmaceutically acceptable salt thereof in the manufacture of a therapeutic agent for inflammatory bowel disease. [25] The use according to [24], wherein the inflammatory bowel disease is ulcerative colitis or Crohn's disease. [26] Use of the compound according to any one of [1] to [7] or a pharmaceutically acceptable salt thereof in the manufacture of a fractalkine-CX3CR1 pathway inhibitor. [27] Use of the compound according to any one of [1] to [7] or a pharmaceutically acceptable salt thereof in the production of a fractalkine inhibitor. [28] Use of the compound according to any one of [1] to [7] or a pharmacologically acceptable salt thereof in the manufacture of a CX3CR1 inhibitor. About.
  • the compound according to the present invention has an inhibitory action in the fractalkine-CX3CR1 pathway. Therefore, the compound according to the present invention has applicability as a therapeutic agent for inflammatory bowel disease.
  • Example 4 is a graph showing the results of Test Example 2 for the compounds of Examples 3, 6 and 11.
  • 6 is a graph showing the results of Test Example 2 for the compounds of Examples 2, 7, and 8.
  • 2 is a graph showing the results of Test Example 2 for the compounds of Examples 1, 9, and 10. It is a graph showing the result of the test example 2 regarding the compound of Example 12, 13 and 14.
  • the present invention is not limited to a specific crystal form, although a crystal polymorph may exist, and a single substance of any crystal form may be a mixture.
  • the present invention includes amorphous forms, and the compounds according to the present invention include anhydrides, hydrates and solvates.
  • C 1-6 alkyl group means a linear or branched alkyl group having 1 to 6 carbon atoms. Specific examples thereof include a methyl group, an ethyl group, 1 -Propyl group, 2-propyl group, 2-methyl-1-propyl group, 2-methyl-2-propyl group, 1-butyl group, 2-butyl group, 1-pentyl group, 2-pentyl group, 3-pentyl Group, 1-hexyl group, 2-hexyl group, 3-hexyl group and the like.
  • C 3-8 cycloalkyl group means a monocyclic saturated aliphatic hydrocarbon group having 3 to 8 carbon atoms. Specific examples thereof include a cyclopropyl group, a cyclobutyl group, A cyclopentyl group, a cyclohexyl group, a cycloheptyl group, a cyclooctyl group, etc. are mentioned.
  • C 3-8 cycloalkenyl group means a monocyclic aliphatic hydrocarbon group having 3 to 8 carbon atoms and containing 1 to 4 double bonds in the ring. Specific examples include a cyclopropenyl group, a cyclobutenyl group, a cyclopentenyl group, a cyclohexenyl group, a cycloheptenyl group, and a cyclooctenyl group.
  • halogen atom means a fluorine atom, a chlorine atom, a bromine atom or an iodine atom.
  • R in the compound represented by the formula (1) is selected from an unsubstituted or substituted C 1-6 alkyl group having 1 to 3 substituents selected from Substituent Group A, unsubstituted or Substituent Group A C 3-8 refers to a cycloalkyl group or an unsubstituted or C 3-8 cycloalkenyl group which 1-3 have a substituent selected from substituent group a, and 1-3 have the substituents.
  • R represents a fluorobutyl group, a pentyl group, a cyclohexyl group, a difluorocyclohexyl group, a cyclopentenyl group or a cyclohexenyl group.
  • X in the compound represented by the formula (1) means a C 1-6 alkyl group.
  • X represents a methyl group.
  • Y and Z in the compound represented by the formula (1) are the same or different and each is a C 1-6 alkyl group having 1 to 3 substituents selected from a halogen atom or an unsubstituted or substituted group B Means.
  • Y represents a chlorine atom.
  • Z represents a chlorine atom, a methyl group, a difluoromethyl group or a trifluoromethyl group.
  • N in the compound represented by the formula (1) means 0 or 1, preferably 1.
  • Substituent group A consists of a halogen atom, preferably a fluorine atom.
  • the substituent group B is composed of a halogen atom, preferably a fluorine atom, a chlorine atom or a bromine atom, more preferably a fluorine atom.
  • the “pharmacologically acceptable salt” in the present specification is not particularly limited as long as it forms a salt with the compound represented by the formula (1) and is pharmacologically acceptable.
  • inorganic acid salts include, for example, hydrochloride, hydrobromide, sulfate, nitrate, phosphate and the like
  • organic acid salts include, for example, acetate, succinate and fumarate.
  • Preferred examples of the inorganic base salt include alkali metal salts such as sodium salt and potassium salt, alkaline earth metal salts such as calcium salt and magnesium salt, aluminum salt, ammonium salt and the like, and preferred examples of organic base salts Examples thereof include diethylamine salt, diethanolamine salt, meglumine salt, N, N′-dibenzylethylenediamine salt and the like.
  • acidic amino acid salts include aspartate and glutamate
  • basic amino acid salts include arginine salt, lysine salt and ornithine salt.
  • the compound represented by the formula (1) can be produced by the method described below, and can also be produced by a person skilled in the art improving the method described below based on ordinary knowledge. However, the manufacturing method of the compound represented by Formula (1) is not limited to these.
  • the compound represented by the formula (1) (hereinafter also referred to as the compound (1)) is prepared by using the intermediate represented by the formula (2) as a starting material, step A, step B and step C described in detail below. It can be manufactured after that. [Wherein R, X, Y, Z and n are as defined above. ]
  • each step may be appropriately changed based on the ordinary knowledge of those skilled in the art, and after each step, it may be purified by a method known to those skilled in the art or may be isolated and purified. You may proceed to the next step without doing so.
  • the solvent used is not particularly limited as long as it can dissolve the starting materials to some extent and does not inhibit the reaction.
  • N, N-dimethylformamide, N, N-dimethylacetamide, 1 -Amides such as methylpyrrolidinone, ethers such as tetrahydrofuran, sulfoxides such as dimethyl sulfoxide and the like, and N, N-dimethylformamide is preferred.
  • benzotriazol-1-yloxytris pyrrolidino
  • PyBOP bis (2-oxo-3-oxazolidinyl) phosphinic chloride
  • BOP-Cl bis (2-oxo-3-oxazolidinyl) phosphinic chloride
  • Benzotriazol-1-yloxytris dimethylamino
  • diethyl cyanophosphate PyBOP or BOP-Cl is preferable, and PyBOP is most preferable.
  • Examples of the base to be used include triethylamine and diisopropylethylamine, and triethylamine is preferable.
  • the reaction temperature varies depending on the starting materials, the solvent, the condensing agent and the base, but is usually ⁇ 20 ° C. to 100 ° C., preferably 0 ° C. to 60 ° C.
  • reaction time varies depending on the starting material, solvent, condensing agent and base, but is usually 30 minutes to 5 days, preferably 1 hour to 3 days.
  • Step B Arylmethylation reaction [Wherein R, X, Y, Z and n are as defined above. W 1 represents a halogen atom, an alkylsulfonyloxy group or an arylsulfonyloxy group. ]
  • This step is a step of producing compound (6) by reacting compound (4) with compound (5) in the presence of a base in an inert solvent.
  • the solvent used is not particularly limited as long as it dissolves the starting materials to some extent and does not inhibit the reaction.
  • N, N-dimethylformamide, N, N-dimethylacetamide examples thereof include amides such as 1-methylpyrrolidinone and sulfoxides such as dimethyl sulfoxide, and N, N-dimethylformamide is preferable.
  • Examples of the base to be used include inorganic bases such as sodium carbonate and potassium carbonate, and potassium carbonate is preferable.
  • the reaction temperature varies depending on the starting materials, the solvent and the base, but is usually ⁇ 20 ° C. to 100 ° C., preferably 0 ° C. to 60 ° C.
  • the reaction time varies depending on the starting materials, the solvent and the base, but is usually 30 minutes to 5 days, and preferably 1 to 24 hours.
  • Step C Determination of tert-butyl group [Wherein R, X, Y, Z and n are as defined above. ]
  • This step is a step of producing compound (1) by reacting compound (6) with an acid in the absence of a solvent or in an inert solvent.
  • the solvent to be used is not particularly limited as long as it dissolves the starting materials to some extent and does not inhibit the reaction.
  • halogenated hydrocarbons such as dichloromethane and chloroform, toluene
  • Examples include dioxane, water, a mixed solvent of dioxane and water, and dichloromethane is preferable.
  • Examples of the acid used include carboxylic acids such as trifluoroacetic acid and inorganic acids such as hydrochloric acid, and trifluoroacetic acid is preferable.
  • the reaction temperature varies depending on the starting materials, the solvent and the acid, but is usually ⁇ 20 ° C. to 100 ° C., preferably 0 ° C. to 40 ° C.
  • reaction time varies depending on the starting materials, solvent and acid, but is usually 30 minutes to 1 day, preferably 1 to 12 hours.
  • Step D Reductive amination reaction [Wherein X, Y and Z are as defined above. ]
  • This step is a step of producing compound (8) by reacting compound (2) with compound (7) and a reducing agent in an inert solvent in the presence or absence of an acid.
  • the solvent used is not particularly limited as long as it dissolves the starting materials to some extent and does not inhibit the reaction.
  • ethers such as tetrahydrofuran, alcohols such as methanol and ethanol, etc. Preferred is tetrahydrofuran or methanol.
  • Examples of the reducing agent used include sodium triacetoxyborohydride, sodium cyanoborohydride, borohydride compounds such as sodium borohydride, and the like, and preferably sodium triacetoxyborohydride.
  • the acid may or may not be used in this step, but when used, the acid used is not particularly limited as long as it does not inhibit the reaction, but is preferably acetic acid.
  • the reaction temperature varies depending on the starting material, solvent, reducing agent and acid, but is usually -20 ° C to 100 ° C, preferably 0 ° C to 60 ° C.
  • reaction time varies depending on the starting material, solvent, reducing agent and acid, but is usually 30 minutes to 5 days, preferably 1 to 48 hours.
  • the reaction can be allowed to proceed by adding an organic amine such as triethylamine to the carboxylic acid forming the salt in an equivalent amount or more. Can do.
  • Step E Hydrogenation reaction From the compound (6) obtained in the step B, a compound (4) from which an arylmethyl group is eliminated can be obtained by a hydrogenation reaction.
  • the compound (4) can be further converted into a compound (6) to which an arylmethyl group having a different substituent is added by Step B.
  • R, Z and n are as defined above.
  • Y 1 and Y 2 have the same meaning as Y above, and Z 1 and Z 2 have the same meaning as Z above. ]
  • This step is a step of producing compound (4) by reacting compound (6) with hydrogen in the presence of a reduction catalyst in an inert solvent to remove the arylmethyl group.
  • the solvent used is not particularly limited as long as it can dissolve the starting materials to some extent and does not inhibit the reaction.
  • alcohols such as methanol and ethanol, tetrahydrofuran , Ethers such as dioxane and dimethoxyethane, and organic acid esters such as ethyl acetate, preferably ethers, alcohols, organic acid esters or a mixed solvent thereof, and most preferred Is methanol or ethanol.
  • Examples of the reduction catalyst used include Pd / C, palladium hydroxide, Raney nickel, platinum oxide, platinum black, and the like, and preferably Pd / C or palladium hydroxide.
  • the reaction temperature varies depending on the starting materials and the solvent, but is usually 0 to 70 ° C, preferably 10 to 50 ° C.
  • the reaction time varies depending on the starting material, the solvent, and the reaction temperature, but is usually 30 minutes to 5 days, and preferably 1 to 3 days.
  • the hydrogen pressure during the reaction is usually 0.5 to 10 atm, preferably 1 to 5 atm.
  • the compound obtained in this step can be used in the next step, usually only by filtering the catalyst.
  • Step F Compound (1) can also be obtained by Step F. [Wherein R, X, Y, Z and n are as defined above. ]
  • Step F-1 Amidation reaction This step is a step of producing a compound (11) by dehydration condensation of the carboxyl group of the compound (8) and the amino group of the compound (10). Can be performed.
  • Step F-2 Detert-butylation and detert-butyloxycarbonylation reaction This step is a step for producing compound (12) by reacting compound (11) with an acid. It can be done by a method.
  • Step F-3 Reductive amination reaction
  • This step is a step for producing compound (1) by reacting compound (12) with aldehyde compound (13) in the presence of a reducing agent.
  • the method can be used.
  • Compound (2) can also be produced by the following step G. [Wherein X is as defined above. V represents a hydrogen atom or a methoxy group. W 2 represents a halogen atom. ]
  • Step G-1 Esterification Reaction This step is a step for producing compound (16) by reacting compound (14) with compound (15) in the presence of a base in an inert solvent. This step can be performed according to step B.
  • Step G-2 Cycloaddition reaction
  • compound (16) is reacted with N- (methoxymethyl) -N- (trimethylsilylmethyl) benzylamine in the presence of an acid in an inert solvent to give compound (17) is a process of manufacturing.
  • the solvent used is not particularly limited as long as it dissolves the starting materials to some extent and does not inhibit the reaction.
  • ethers such as tetrahydrofuran, halogenated compounds such as dichloromethane and chloroform.
  • hydrocarbons such as benzene and toluene, and preferred are dichloromethane and toluene, and mixed solvents thereof.
  • the acid used is not particularly limited as long as it is usually used by those skilled in the art, but trifluoroacetic acid is preferred.
  • the reaction temperature varies depending on the starting material, solvent, reducing agent, and acid, but is usually ⁇ 20 ° C. to 60 ° C., preferably 10 ° C. to 40 ° C.
  • the reaction time varies depending on the starting material, solvent, reducing agent, and acid, but is usually 30 minutes to 5 days, and preferably 1 to 24 hours.
  • N- (methoxymethyl) -N- (trimethylsilylmethyl) benzylamine is added dropwise while paying attention to the exotherm after mixing the compound (16), solvent and acid. Is preferred.
  • Step G-3 Alkylation reaction This step is a step of producing compound (18) by reacting compound (17) with a base in an inert solvent and then reacting with tert-butyl bromoacetate.
  • the solvent used is not particularly limited as long as it dissolves the starting materials to some extent and does not inhibit the reaction.
  • ethers such as tetrahydrofuran and diethyl ether, and fats such as hexane.
  • Preferred are mixed solvents of tetrahydrofuran, tetrahydrofuran and hexane.
  • Preferred examples of the base to be used include lithium salts of organic amines such as lithium diisopropylamide and lithium bis (trimethylsilyl) amide, and more preferred are lithium diisopropylamide and lithium bis (trimethylsilyl) amide.
  • reaction temperature varies depending on the starting materials, solvent and base, it is generally ⁇ 100 ° C. to 50 ° C., preferably ⁇ 80 ° C. to ⁇ 40 ° C., and most preferably ⁇ 80 ° C. to ⁇ 70 ° C. .
  • the reaction time varies depending on the starting materials, the solvent and the base, but is usually 30 minutes to 5 days, preferably 1 to 24 hours, and most preferably 2 to 5 hours.
  • Step G-4 Hydrogenation Reaction This step is a step of removing benzyl group by reacting compound (18) with hydrogen in an inert solvent in the presence of a reduction catalyst.
  • this process can be performed according to the said process E.
  • Step G-5 Chiral Resolution
  • the racemate of compound (2) is chirally resolved to obtain compound (2).
  • the solvent used for the split mobile phase and sample charge is not particularly limited as long as it dissolves the starting materials to some extent and does not adversely affect the column or sample.
  • Alcohols such as methanol, ethanol, 2-propanol, hexane, acetonitrile, tetrahydrofuran, trifluoroacetic acid, diethylamine or a mixed solvent thereof, and the like, preferably acetonitrile, ethanol, a mixed solvent of ethanol and hexane. is there.
  • Examples of the column used for the resolution include various commercially available columns for optical resolution, preferably CHIRALPAK AD-H, CHIRALPAK IA, and CHIRALCEL OZ-H manufactured by Daicel Chemical Industries.
  • the column temperature during the division is preferably 10 ° C to 45 ° C.
  • Step H Compound (3) used in step A and the like can also be produced by the following step H. [Wherein R and n are as defined above. ]
  • Step H-1 Reductive amination reaction
  • compound (19) and compound (13) are reacted in an inert solvent in the presence or absence of an acid in the presence of a reducing agent. 20), which can be performed according to Step D.
  • Step H-2 Determination of tert-butyloxycarbonyl group
  • compound (20) is reacted with an acid in the absence of a solvent or in an inert solvent to remove the tert-butyloxycarbonyl group,
  • This is a step for producing compound (3), which can be carried out according to step C.
  • Compound (2) can also be produced according to the following step I, starting from the racemate of compound (2). [Wherein X and V are as defined above. ]
  • Step I-1 Benzyloxycarbonyl group introduction reaction This step introduces a benzyloxycarbonyl group by reacting the racemate of compound (2) with benzylchloroformate in the presence of a base in an inert solvent. It is a process.
  • the solvent used is not particularly limited as long as it can dissolve the starting materials to some extent and does not inhibit the reaction.
  • ethers such as tetrahydrofuran and 1,4-dioxane, water , N, N-dimethylformamide, dichloromethane, acetone, and a mixed solvent thereof, and the like, and a mixed solvent of water and acetone is preferable.
  • Examples of the base used include inorganic bases such as sodium hydroxide, potassium hydroxide, sodium hydrogen carbonate, sodium carbonate and potassium carbonate, and organic amines such as triethylamine and diisopropylethylamine. , Sodium hydroxide.
  • the reaction temperature varies depending on the starting materials, solvent and base, but is usually ⁇ 30 ° C. to 20 ° C., preferably ⁇ 10 ° C. to 15 ° C.
  • the reaction time varies depending on the starting materials, the solvent and the base, but is usually 30 minutes to 5 days, and preferably 1 to 24 hours.
  • Step I-2 Esterification Reaction
  • This step is a step for producing compound (22) by reacting compound (21) with benzyl halide in the presence of a base in an inert solvent. This step can be performed according to step B.
  • Step I-3 Chiral Resolution
  • compound (22) is chirally resolved to obtain a chiral form of compound (22). This step can be performed according to Step G-5.
  • Step I-4 Hydrogenation Reaction This step is a step of obtaining a compound (2) by reacting a chiral compound of the compound (22) with hydrogen in an inert solvent in the presence of a reduction catalyst. This step can be performed according to step E.
  • Compound (2) can also be produced by the following step J using compound (18) as a starting material. [Wherein, X and V are as defined above. ]
  • Step J-1 Benzyloxycarbonyl group introduction reaction
  • compound (18) is reacted with benzyl chloroformate in an inert solvent to replace the benzyl group with a benzyloxycarbonyl group.
  • the solvent used is not particularly limited as long as it dissolves the starting materials to some extent and does not inhibit the reaction.
  • dichloromethane is preferable.
  • the reaction temperature varies depending on the starting materials and the solvent, but is usually ⁇ 20 ° C. to 60 ° C., preferably 0 ° C. to 40 ° C.
  • the reaction time varies depending on the starting materials and the solvent, but is usually 30 minutes to 5 days, and preferably 1 to 24 hours.
  • Step J-2 Chiral Resolution
  • compound (22) is chirally resolved to obtain a chiral form of compound (22). This step can be performed according to Step G-5.
  • Step J-3 Hydrogenation Reaction
  • This step is a step of obtaining a compound (2) by reacting a chiral compound of the compound (22) with hydrogen in an inert solvent in the presence of a reduction catalyst. This step can be performed according to step E.
  • the target compound in each step can be collected from the reaction mixture according to a conventional method.
  • the reaction mixture may be allowed to warm to room temperature if desired, or ice-cooled, neutralizing acid, alkali, oxidizing agent or reducing agent as appropriate, and immiscible with water and ethyl acetate.
  • the organic solvent which does not react with the target compound is added, and the layer containing the target compound is separated.
  • a solvent that is immiscible with the obtained layer and does not react with the target compound is added, the layer containing the target compound is washed, and the layer is separated.
  • the target compound can be collected by drying using a drying agent such as anhydrous magnesium sulfate or anhydrous sodium sulfate and distilling off the solvent.
  • a drying agent such as anhydrous magnesium sulfate or anhydrous sodium sulfate and distilling off the solvent.
  • the said layer is an aqueous layer, after desalting electrically, it can extract
  • the target compound is collected only by distilling off substances other than the target compound (eg, solvent, reagent, etc.) under normal pressure or reduced pressure. can do.
  • the target compound is obtained by filtration.
  • the target compound collected by filtration is washed with an appropriate organic or inorganic solvent and dried to treat the mother liquor in the same manner as in the case where the whole reaction mixture is a liquid, thereby further collecting the target compound. it can.
  • the reagent or catalyst exists as a solid, or the reaction mixture as a whole is liquid, and only the reagent or catalyst is precipitated as a solid during the collection process, and the target compound
  • the reagent or catalyst is filtered off by filtration, and the filtered reagent or catalyst is washed with an appropriate organic or inorganic solvent, and the resulting washing solution is combined with the mother liquor, and the resulting mixture is mixed.
  • the target compound can be collected by treating the liquid in the same manner as in the case where the whole reaction mixture is liquid.
  • the target compound when a compound other than the target compound contained in the reaction mixture does not inhibit the reaction in the next step, the target compound can be used in the next step as it is without isolating the target compound.
  • the purity of the target compound can usually be improved by a recrystallization method.
  • a single solvent or a mixed solvent that does not react with the target compound can be used. Specifically, first, the target compound is dissolved in a single or a plurality of solvents that do not react with the target compound at room temperature or under heating. The resulting liquid mixture is cooled with ice water or the like, or stirred or left at room temperature to crystallize the target compound from the liquid mixture.
  • the collected target compound can improve the purity of the target compound by various chromatographic methods.
  • silica gel 60 70-230 mesh or 340-400 mesh
  • BW-300 300 mesh weakly acidic silica gel manufactured by Fuji Silysia Chemical Ltd.
  • propylamine coated silica gel 200-350 mesh
  • Fuji Silysia Chemical Co., Ltd. or disposable medium pressure preparative packing manufactured by Yamazen Co., Ltd.
  • NH silica gels such as a column (high flash amino) can also be used.
  • NAM-200H or NAM-300H manufactured by Nam Research Laboratory, or YMC GEL ODS-A manufactured by YMC is used. You can also. Disposable medium pressure preparative packed columns (High Flush) manufactured by Yamazen Co., Ltd., manufactured by Wako Pure Chemical Industries, Ltd., biotage, Inc., or Grace Co., which are preliminarily packed with the above-described fillers can also be used.
  • Disposable medium pressure preparative packed columns (High Flush) manufactured by Yamazen Co., Ltd., manufactured by Wako Pure Chemical Industries, Ltd., biotage, Inc., or Grace Co., which are preliminarily packed with the above-described fillers can also be used.
  • the purity of the target compound can also be improved by distillation.
  • the target compound can be distilled by reducing the pressure of the target compound at room temperature or under heating.
  • the above is a representative example of the production method of compound (1), but the raw material compound and various reagents in the production of compound (1) may form solvates such as salts and hydrates. Also, it varies depending on the starting material, the solvent used, etc., and is not particularly limited as long as it does not inhibit the reaction. It goes without saying that the solvent to be used is not particularly limited as long as it varies depending on starting materials, reagents and the like, and can dissolve the starting material to some extent without inhibiting the reaction.
  • compound (1) When compound (1) is obtained as a free form, it can be converted into a salt or a solvate that may be formed by compound (1) according to a conventional method.
  • compound (1) When compound (1) is obtained as a salt or solvate, the free form of compound (1) can be converted according to a conventional method.
  • various isomers for example, geometric isomers, optical isomers, rotational isomers, stereoisomers, tautomers, etc.
  • obtained for the compound (1) can be obtained by conventional separation means such as recrystallization, It can be purified and isolated by using a diastereomeric salt method, an enzyme resolution method, and various types of chromatography (for example, thin layer chromatography, column chromatography, gas chromatography, etc.).
  • Compound (1) or a pharmacologically acceptable salt thereof can be formulated by a conventional method.
  • the dosage form include oral preparations (tablets, granules, powders, capsules, syrups, etc.). , Injections (for intravenous administration, intramuscular administration, subcutaneous administration, intraperitoneal administration), external preparations (transdermal absorption preparations (ointments, patches, etc.), eye drops, nasal drops, suppositories, etc. ).
  • solid preparations such as tablets, capsules, granules and powders are usually 0.001 to 99.5% by weight, preferably 0.01 to 90% by weight of the compound (1) or a pharmaceutically acceptable product thereof.
  • the resulting salt can be included.
  • compound (1) or a pharmaceutically acceptable salt thereof if necessary, an excipient, a binder, a disintegrant, a lubricant, a colorant, etc.
  • an excipient if necessary, an excipient, a binder, a disintegrant, a lubricant, a colorant, etc.
  • Tablets, granules, powders, capsules and the like may be coated with a film as necessary.
  • excipient examples include lactose, corn starch, crystalline cellulose, and the like.
  • binder examples include hydroxypropylcellulose and hydroxypropylmethylcellulose.
  • disintegrant examples include carboxymethylcellulose calcium and croscarmette. Examples include sodium loose.
  • Examples of the lubricant include magnesium stearate and calcium stearate, and examples of the colorant include titanium oxide.
  • Examples of the film coating agent include hydroxypropylcellulose, hydroxypropylmethylcellulose, methylcellulose and the like.
  • any of the above-mentioned additives is not limited to these.
  • a pH adjusting agent, a buffering agent, a suspending agent, a solubilizing agent, an antioxidant, a preservative (preservative), an isotonic agent, and the like can be added to produce a conventional method. Alternatively, it may be freeze-dried to obtain a freeze-dried preparation that is dissolved at the time of use.
  • These injections can be administered intravenously, subcutaneously, intramuscularly and the like.
  • pH adjusting agents and buffering agents include organic acids or inorganic acids and / or salts thereof.
  • suspending agents include methylcellulose, polysorbate 80, sodium carboxymethylcellulose, and the like.
  • glucose, sodium chloride, mannitol and the like can be mentioned, but of course not limited thereto.
  • injection solutions can contain usually 0.000001 to 99.5% by weight, preferably 0.00001 to 90% by weight of the compound (1) or a pharmacologically acceptable salt thereof.
  • a base material is added to the compound (1) or a pharmacologically acceptable salt thereof, and the above-described emulsifier, preservative, pH adjuster, colorant as necessary.
  • a base material is added to the compound (1) or a pharmacologically acceptable salt thereof, and the above-described emulsifier, preservative, pH adjuster, colorant as necessary.
  • the like, and the like can be produced by a conventional method such as transdermal preparations (ointments, patches, etc.), eye drops, nasal drops, suppositories, and the like.
  • various raw materials usually used for pharmaceuticals, quasi drugs, cosmetics and the like can be used.
  • animal and vegetable oils, mineral oils, ester oils, waxes, higher alcohols, purified water And other raw materials can be used.
  • These external preparations can contain usually 0.000001 to 99.5% by weight, preferably 0.00001 to 90% by weight of the compound (1) or a pharmacologically acceptable salt thereof.
  • the dose of the pharmaceutical agent according to the present invention usually varies depending on symptoms, age, sex, weight, etc., but may be an amount sufficient for producing a desired effect.
  • about 0.1 to 5000 mg (preferably 0.5 to 1000 mg, more preferably 1 to 600 mg) per day is used once or during a day or 2 to 6 per day. Used in divided times.
  • the invention also includes isotope-labeled compounds of compound (1), which have one or more atoms having an atomic mass or mass number different from the atomic mass or mass number normally found in nature. It is the same as compound (1) except that it is replaced by an atom.
  • the isotopes that can be incorporated into the compound (1) are, for example, isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, fluorine, iodine, and chlorine. 2 H, 3 H, 11 C, 14 C, 13 N, 15 O, 18 F, 32 P, 35 S, 123 I, 125 I and the like are included.
  • Isotopically-labeled compounds of the present invention eg, compounds incorporating a radioactive isotope such as 3 H and / or 14 C
  • 3 H and 14 C are considered useful because of their ease of preparation and detection.
  • the isotopes 11 C and 18 F are considered useful in PET (Positron Emission Tomography) and the isotope 125 I is considered useful in SPECT (Single Photon Emission Computed Tomography), all useful in brain imaging. It is.
  • isotope-labeled compound of compound (1) undergoes the procedures disclosed in the following schemes and / or examples using readily available isotope-labeled reagents in place of non-isotopically labeled reagents. Can be prepared uniformly.
  • Compound (1) can be used as a chemical probe for capturing a target protein of a bioactive low molecular weight compound. That is, the compound (1) is different from the structural part essential for the expression of the activity of the compound in the J. Mass Spectrum. Soc. Jpn. Vol. 51, No. 5 2003, p492-498 or WO2007 / 139149 can be converted into affinity chromatography, photoaffinity probe, etc. by introducing a labeling group, a linker or the like by the method described in WO2007 / 139149.
  • Examples of the labeling group and linker used for the chemical probe include groups shown in the following groups (1) to (5).
  • Photoaffinity labeling groups for example, benzoyl group, benzophenone group, azide group, carbonyl azide group, diaziridine group, enone group, diazo group and nitro group
  • chemical affinity groups for example, alpha carbon atom is halogen
  • a protein labeling group such as a ketone group substituted with an atom, a carbamoyl group, an ester group, an alkylthio group, a Michael acceptor such as an ⁇ , ⁇ -unsaturated ketone, an ester, and an oxirane group
  • a cleavable linker such as —SS—, —O—Si—O—, monosaccharide (glucose group, galactose group, etc.) or disaccharide (lactose etc.), and oligopeptide cleavable by enzymatic reaction Link
  • a probe prepared by introducing a labeling group selected from the group consisting of the above (1) to (5) into the compound (1) according to the method described in the above literature is a new drug discovery target. It can be used as a chemical probe for identifying a labeled protein useful for searching and the like.
  • Compound (1) can be produced, for example, by the method described in the following examples, and the effect of compound (1) can be confirmed by the method described in the following test examples. However, these are illustrative, and the present invention is not limited to the following specific examples in any case.
  • Example 1a tert-butyl 4- ⁇ [(benzyloxy) carbonyl] amino ⁇ piperidine-1-carboxylate tert-butyl 4-aminopiperidine-1-carboxylate (10 g, 49.9 mmol), N, N- Diisopropylethylamine (26 ml, 149 mmol), benzyl chloroformate (8.5 ml, 59.5 mmol), and dichloromethane (dehydrated) (300 ml) were mixed under ice cooling. The resulting mixture was stirred at room temperature for 1 hour. Saturated aqueous sodium hydrogen carbonate solution was added to the reaction mixture, and the mixture was extracted 3 times with dichloromethane.
  • Example 1b Benzyl N- (piperidin-4-yl) carbamate tert-butyl 4- ⁇ [(benzyloxy) carbonyl] amino ⁇ piperidine-1-carboxylate (13.1 g, 39.39) obtained in Example 1a. 2 mmol), a mixture of 5N aqueous hydrochloric acid (40 ml, 200 mmol) and methanol (40 ml) was stirred at room temperature for 23 hours. To the reaction mixture was added 5N aqueous sodium hydroxide solution (40 ml) under ice cooling. Water and the solvent were distilled off from the reaction mixture while azeotroping with ethanol.
  • Example 1c Chiral body of benzyl N- [1- (2-fluoropentyl) piperidin-4-yl] carbamate (5S)-( ⁇ )-2,2,3-trimethyl-5-benzyl-4-imidazo Lydinone dichloroacetic acid (90 mg, 0.259 mmol), N-fluorobenzenesulfonimide (484 mg, 1.53 mmol), 2-propanol (0.4 ml) and tetrahydrofuran (dehydrated) (3.6 ml) were mixed at room temperature.
  • Example 1d Chiral form of 1- (2-fluoropentyl) piperidin-4-amine Chiral form of benzyl N- [1- (2-fluoropentyl) piperidin-4-yl] carbamate obtained in Example 1c ( A mixture having a shorter retention time (318 mg, 0.986 mmol), 10% Pd / C (100 mg) and methanol (7 ml) was stirred at room temperature for 2 hours under a hydrogen atmosphere. The reaction vessel was purged with nitrogen, 10% Pd / C was removed by filtration, and the solvent was distilled off to obtain the title compound (249 mg).
  • Example 1e Benzyl (2E) -but-2-enoate Crotonic acid (70 g, 812 mmol) was dissolved in N, N-dimethylformamide (467 ml), cooled in an ice bath under nitrogen, and potassium carbonate (61.6 g). , 447 mmol). To the reaction mixture, benzyl bromide (91.7 ml, 772 mmol) was added dropwise over 20 minutes. The reaction mixture was stirred at room temperature for 18 hours. Ethyl acetate was added to the reaction mixture, and the mixture was filtered through celite.
  • Example 1f Benzyl (3RS, 4SR) -1-benzyl-4-methylpyrrolidine-3-carboxylate
  • the benzyl (2E) -but-2-enoate obtained in Example 1e (20.5 g, 116 mmol) was dissolved in dichloromethane. (5 ml) and the mixture was cooled in an ice bath with stirring. Trifluoroacetic acid (257 ⁇ l, 3.47 mmol) was added, and the inner temperature was 62 ° C. while washing N- (methoxymethyl) -N- (trimethylsilylmethyl) benzylamine (33.1 g, 139 mmol) with dichloromethane (25 ml). Was added dropwise to the reaction solution over 15 minutes.
  • Example 1g Benzyl (3RS, 4SR) -1-benzyl-3- [2- (tert-butoxy) -2-oxoethyl] -4-methylpyrrolidine-3-carboxylate
  • the benzyl (3RS obtained in Example 1f) , 4SR) -1-benzyl-4-methylpyrrolidine-3-carboxylate (30 g, 97.4 mmol) was dissolved in tetrahydrofuran (300 ml) and cooled to ⁇ 70 ° C. with stirring under nitrogen.
  • the reaction mixture was then immediately diluted with water and ethyl acetate was added.
  • the organic layer was washed with saturated brine and 5N aqueous hydrochloric acid solution, dried over magnesium sulfate, filtered and concentrated.
  • the residue was purified by silica gel column chromatography (elution solvent: ethyl acetate / heptane).
  • Example 1h 1,3-dibenzyl (3RS, 4SR) -3- [2- (tert-butoxy) -2-oxoethyl] -4-methylpyrrolidine-1,3-dicarboxylate
  • the benzyl (3RS, 4SR) -1-benzyl-3- [2- (tert-butoxy) -2-oxoethyl] -4-methylpyrrolidine-3-carboxylate (11.7 g, 27.6 mmol) (117 ml) and benzyl chloroformate (23.7 ml, 166 mmol) was added dropwise to the reaction solution over 20 minutes so that the internal temperature did not exceed 22 ° C.
  • Example 1i (3S, 4R) -3- [2- (tert-Butoxy) -2-oxoethyl] -4-methylpyrrolidine-3-carboxylic acid 1,3-dibenzyl (3RS, obtained in Example 1h) 4SR) -3- [2- (tert-butoxy) -2-oxoethyl] -4-methylpyrrolidine-1,3-dicarboxylate (9.1 g) was subjected to optical resolution under the following two conditions A or B. went.
  • Example 1j (3S, 4R) -1-Benzyl-3- [2- (tert-butoxy) -2-oxoethyl] -4-methylpyrrolidine-3-carboxylic acid obtained in Example 1i (3S, 4R ) -3- [2- (tert-butoxy) -2-oxoethyl] -4-methylpyrrolidine-3-carboxylic acid (1.8 g, 7.4 mmol), benzaldehyde (1.51 ml, 14.8 mmol), acetic acid ( A mixture of 0.635 ml, 11.1 mmol), sodium triacetoxyborohydride (3.14 g, 14.8 mmol) and methanol (35 ml) was heated at 40 ° C.
  • Example 1k tert-butyl 2-[(3S, 4R) -1-benzyl-3- ⁇ [1- (2-fluoropentyl) piperidin-4-yl] carbamoyl ⁇ -4-methylpyrrolidin-3-yl ] Chiral Acetate (3S, 4R) -1-Benzyl-3- [2- (tert-butoxy) -2-oxoethyl] -4-methylpyrrolidine-3-carboxylic acid (300 mg, 0) obtained in Example 1j .9 mmol), 1- (2-fluoropentyl) piperidin-4-amine chiral compound obtained in Example 1d (182 mg, 0.967 mmol), triethylamine (0.376 ml, 2.7 mmol), PyBOP (656 mg, 1 .26 mmol) and N, N-dimethylformamide (4.5 ml) was stirred at room temperature for 61 hours 30 minutes.
  • Triethylamine (0.207 ml, 1.49 mmol) and PyBOP (360 mg, 0.69 mmol) were further added, and the mixture was stirred for 4 hours 30 minutes. Water was added to the reaction mixture, and the mixture was extracted twice with ethyl acetate. The organic layer was washed with a saturated aqueous ammonium chloride solution and dried over anhydrous magnesium sulfate, and the solvent was distilled off. The residue was purified by silica gel column chromatography (NH silica gel, elution solvent: ethyl acetate / heptane) to obtain the title compound (161 mg, yield 35.5%).
  • Example 1m 2-[(3S, 4R) -1- ⁇ [2-Chloro-6- (trifluoromethyl) phenyl] methyl ⁇ -3- ⁇ [1- (2-fluoropentyl) piperidine-4- [Ill] carbamoyl ⁇ -4-methylpyrrolidin-3-yl] acetic acid chiral tert-butyl 2-[(3S, 4R) -1- ⁇ [2-chloro-6- (trifluoromethyl) obtained in Example 11 ) Phenyl] methyl ⁇ -3- ⁇ [1- (2-fluoropentyl) piperidin-4-yl] carbamoyl ⁇ -4-methylpyrrolidin-3-yl] acetate chiral form (153 mg, 0.252 mmol), trifluoro A mixture of acetic acid (2 ml, 26.9 mmol) and dichloromethane (dehydrated) (2 ml) was stirred at room temperature for 2 hours and 35 minutes.
  • Example 2a 4,4-Difluoro-N-methoxy-N-methylcyclohexane-1-carboxamide ethyl 4,4-difluorocyclohexane-1-carboxylate (1.9 g, 9.88 mmol) in tetrahydrofuran (60 ml) The mixture was cooled to ⁇ 70 ° C. and N, O-dimethylhydroxyamine hydrochloride (1.44 g, 14.8 mmol) was added. Further, 1.05M n-propylmagnesium bromide (24.2 ml, 25.2 mmol) was added dropwise to the reaction mixture at ⁇ 55 ° C.
  • Example 2b 4,4-Difluorocyclohexane-1-carbaldehyde 4,4-Difluoro-N-methoxy-N-methylcyclohexane-1-carboxamide (1.7 g, 8.21 mmol) obtained in Example 2a, A mixture of tetrahydrofuran (60 ml) was cooled to ⁇ 70 ° C., 1.0 M diisobutylaluminum hydride / toluene solution (9.85 ml, 9.85 mmol) was added, and the reaction mixture was stirred at ⁇ 60 ° C. for 35 minutes.
  • Example 2c tert-Butyl N- ⁇ 1-[(4,4-difluorocyclohexyl) methyl] piperidin-4-yl ⁇ carbamate
  • Crude of 4,4-difluorocyclohexane-1-carbaldehyde obtained in Example 2b The mixture of the product (1.4 g) and tetrahydrofuran (100 ml) was cooled to 0 ° C., tert-butyl N- (piperidin-4-yl) carbamate (2.27 g, 11.3 mmol) was added thereto, and the mixture was stirred for 20 minutes.
  • Example 2d 1-[(4,4-Difluorocyclohexyl) methyl] piperidin-4-amine tert-Butyl N- ⁇ 1-[(4,4-difluorocyclohexyl) methyl] piperidine-obtained in Example 2c
  • 4-yl ⁇ carbamate 650 mg, 1.96 mmol
  • methanol 11 ml
  • 4N hydrogen chloride / 1,4-dioxane solution 11 ml, 43 mmol
  • Example 2e (4-Methoxyphenyl) methyl (2E) -but-2-enoate
  • Crotonic acid (17.2 g, 200 mmol) was cooled to N, N-dimethylformamide (100 ml) in an ice bath under nitrogen.
  • Dissolve and add powdered potassium carbonate (15.2 g, 110 mmol).
  • the mixture was stirred for 30 minutes before 4-methoxybenzyl chloride (29.8 g, 190 mmol) was added dropwise over 15 minutes.
  • the reaction mixture was stirred at room temperature for 4 hours and at 45 ° C. for 14 hours.
  • Ethyl acetate (500 ml) and water (200 ml) were added to the reaction solution.
  • Example 2f (4-Methoxyphenyl) methyl (3RS, 4SR) -1-benzyl-4-methylpyrrolidine-3-carboxylate Obtained in Example 2e by a method similar to that described in Example 1f. The title compound (57.86 g, yield: 86.5%) was obtained from (4-methoxyphenyl) methyl (2E) -but-2-enoate (40.6 g, 197 mmol).
  • Example 2g (4-Methoxyphenyl) methyl (3RS, 4SR) -1-benzyl-3- [2- (tert-butoxy) -2-oxoethyl] -4-methylpyrrolidine-3-carboxylate
  • Example 1g From (4-methoxyphenyl) methyl (3RS, 4SR) -1-benzyl-4-methylpyrrolidine-3-carboxylate (56.7 g, 166 mmol) obtained in Example 2f by a method similar to that described in The title compound (60.3 g, yield: 80.1%) was obtained.
  • Example 2h 1-Benzyl 3- (4-methoxyphenyl) methyl (3RS, 4SR) -3- [2- (tert-butoxy) -2-oxoethyl] -4-methylpyrrolidine-1,3-dicarboxyl Rate (4-Methoxyphenyl) methyl (3RS, 4SR) -1-benzyl-3- [2- (tert-butoxy) -2-] obtained in Example 2g by a method similar to that described in Example 1h The title compound (15 g, yield: 65.1%) was obtained from oxoethyl] -4-methylpyrrolidine-3-carboxylate (21 g, 46.3 mmol).
  • HPLC CHIRALPAK AD-H (2 cm
  • Lot B is a collection of 3 fractions during column purification, and was collected after confirming that the chemical shift of each fraction was the same as the chemical shift of lot A.
  • Example 2m 2-[(3S, 4R) -1-[(2,6-dichlorophenyl) methyl] -3-( ⁇ 1-[(4,4-difluorocyclohexyl) methyl] piperidin-4-yl ⁇ Carbamoyl) -4-methylpyrrolidin-3-yl] acetic acid
  • Example 3a tert-Butyl 4-[(3S, 4R) -1-benzyl-3- [2- (tert-butoxy) -2-oxoethyl] -4-methylpyrrolidine-3-amido] piperidine-1- Carboxylate (3S, 4R) -1-benzyl-3- [2- (tert-butoxy) -2-oxoethyl] -4-methylpyrrolidine-3-carboxylic acid (942 mg, 942 mg, obtained in a similar manner as Example 1j 2.83 mmol) in N, N-dimethylformamide (20 ml) in tert-butyl 4-aminopiperidine-1-carboxylate (849 mg, 4.24 mmol), triethylamine (1.18 ml, 8.48 mmol) and PyBOP (2 .21 g, 4.24 mmol) was added and stirred at room temperature overnight.
  • Example 3c tert-butyl 4-[(3S, 4R) -3- [2- (tert-butoxy) -2-oxoethyl] -1- ⁇ [2-chloro-6- (trifluoromethyl) phenyl] Methyl ⁇ -4-methylpyrrolidine-3-amide] piperidine-1-carboxylate tert-butyl 4-[(3S, 4R) -3- [2- (tert-butoxy) -2-oxoethyl obtained in Example 3b ] -4-methylpyrrolidine-3-amide] piperidine-1-carboxylate (345 mg, 0.811 mmol) in a solution of N, N-dimethylformamide (dehydrated) (10 mL) in 2- (bromomethyl) -1-chloro- 3- (Trifluoromethyl) benzene (443 mg, 1.62 mmol) and potassium carbonate (244 mg) were added, and the mixture was heated at 45 ° C.
  • Example 3d 2-[(3S, 4R) -1- ⁇ [2-Chloro-6- (trifluoromethyl) phenyl] methyl ⁇ -4-methyl-3-[(piperidin-4-yl) carbamoyl] Pyrrolidin-3-yl] acetic acid tert-butyl 4-[(3S, 4R) -3- [2- (tert-butoxy) -2-oxoethyl] -1- ⁇ [2-chloro-6] obtained in Example 3c
  • Example 3e 2-[(3S, 4R) -1- ⁇ [2-Chloro-6- (trifluoromethyl) phenyl] methyl ⁇ -3- ⁇ [1- (Cyclohex-1-ene-1- (Ilmethyl) piperidin-4-yl] carbamoyl ⁇ -4-methylpyrrolidin-3-yl] acetic acid 2-[(3S, 4R) -1- ⁇ [2-chloro-6- (tri Fluoromethyl) phenyl] methyl ⁇ -4-methyl-3-[(piperidin-4-yl) carbamoyl] pyrrolidin-3-yl] acetic acid mixture (344 mg, 0.745 mmol) in tetrahydrofuran (dehydrated) (10 mL) And cyclohex-1-ene-1-carbaldehyde (423 ⁇ l, 3.73 mmol), acetic acid (300 ⁇ l) and sodium triacetoxyborohydride (789 mg, 3.
  • Example 4 Alternative Method of Example 3 Compound 2-[(3S, 4R) -1- ⁇ [2-Chloro-6- (trifluoromethyl) phenyl] methyl ⁇ -3- ⁇ [1- (cyclohex S-1-en-1-ylmethyl) piperidin-4-yl] carbamoyl ⁇ -4-methylpyrrolidin-3-yl] acetic acid
  • Example 4a tert-butyl N- [1- (cyclohex-1-en-1-ylmethyl) piperidin-4-yl] carbamate tert-butyl N- (piperidin-4-yl) carbamate (5.3 g, 26.5 mmol), 1-cyclohexene-1-carboxaldehyde (3.5 g, 31.8 mmol), sodium triacetoxyborohydride (7.29 g, 34.4 mmol), acetic acid (0.5 ml), and tetrahydrofuran (dehydrated) ) (80 ml) was stirred at room temperature for 85 hours 30 minutes. Water and sodium hydrogen carbonate were added to the reaction mixture and stirred, followed by extraction with ethyl acetate twice.
  • Example 4b 1- (Cyclohex-1-en-1-ylmethyl) piperidin-4-amine tert-butyl N- [1- (Cyclohex-1-en-1-ylmethyl) obtained in Example 4a
  • a mixture of piperidin-4-yl] carbamate (7.47 g, 25.4 mmol), 5N aqueous hydrochloric acid (25 ml, 125 mmol), and methanol (100 ml) was stirred at 70 ° C. for 1.5 hours.
  • the reaction mixture was ice-cooled, 5N aqueous sodium hydroxide solution (25 ml, 125 mmol) was added, and the solvent was evaporated. Water was added to the residue and extracted twice with ethyl acetate.
  • Example 4c 1-Benzyl 3- (4-methoxyphenyl) methyl (3RS, 4SR) -3- [2- (tert-butoxy) -2-oxoethyl] -4-methylpyrrolidine-1,3-dicarboxyl (4-Methoxyphenyl) methyl (3RS, 4SR) -1-benzyl-3- [2- (tert-butoxy) -2-oxoethyl] -4-methylpyrrolidine-3-carboxylate obtained in Example 2g ( A solution of 18 g, 39.7 mmol) in dichloromethane (85.7 ml) was adjusted to an internal temperature of 10-20 ° C., and benzyl chloroformate (11.9 ml, 79.4 mmol) was added thereto.
  • Example 4f (3S, 4R) -3- [2- (tert-Butoxy) -2-oxoethyl] -4-methylpyrrolidine-3-carboxylic acid 1-Benzyl 3- (3) obtained by the method of Example 4e 4-methoxyphenyl) methyl (3S, 4R) -3- [2- (tert-butoxy) -2-oxoethyl] -4-methylpyrrolidine-1,3-dicarboxylate (3.3 g, 6.63 mmol) Methanol (70 ml), 10% Pd / C (600 mg) was added, and the mixture was stirred at room temperature for 3 days under a hydrogen atmosphere. Water (70 ml) was added to the reaction solution, stirred and filtered. The filtrate was concentrated to obtain the title compound (1.15 g, yield: 71.3%). 1 H-NMR (400 MHz, D 2 O); consistent with the compound obtained in Example 2j.
  • Example 4i tert-butyl 2-[(3S, 4R) -1- ⁇ [2-chloro-6- (trifluoromethyl) phenyl] methyl ⁇ -3- ⁇ [1- (cyclohex-1-ene -1-ylmethyl) piperidin-4-yl] carbamoyl ⁇ -4-methylpyrrolidin-3-yl] acetate (3S, 4R) -3- [2- (tert-butoxy) -2-oxoethyl obtained in Example 4h ] 1- (Cyclohex-1-en-1-ylmethyl) piperidin-4-amine obtained in Example 4b (240 mg, 1.24 mmol) to 4-methylpyrrolidine-3-carboxylic acid (200 mg, 0.822 mmol).
  • Example 4j 2-[(3S, 4R) -1- ⁇ [2-chloro-6- (trifluoromethyl) phenyl] methyl ⁇ -3- ⁇ [1- (cyclohexyl-1-en-1-ylmethyl) ) Piperidin-4-yl] carbamoyl ⁇ -4-methylpyrrolidin-3-yl] acetic acid tert-butyl 2-[(3S, 4R) -1- ⁇ [2-chloro-6- (tri Fluoromethyl) phenyl] methyl ⁇ -3- ⁇ [1- (cyclohex-1-en-1-ylmethyl) piperidin-4-yl] carbamoyl ⁇ -4-methylpyrrolidin-3-yl] acetate (353 mg,.
  • Example 5 Alternative Method of Example 3 Compound 2-[(3S, 4R) -1- ⁇ [2-Chloro-6- (trifluoromethyl) phenyl] methyl ⁇ -3- ⁇ [1- (cyclohex S-1-en-1-ylmethyl) piperidin-4-yl] carbamoyl ⁇ -4-methylpyrrolidin-3-yl] acetic acid
  • Example 5a tert-butyl 4-[(3RS, 4SR) -3- [2- (tert-butoxy) -2-oxoethyl] -1-[(2,6-dichlorophenyl) methyl] -4-methylpyrrolidine -3-amido] piperidine-1-carboxylate benzyl (3RS, 4SR) -1-benzyl-3- [2- (tert-butoxy) -2-oxoethyl] -4- obtained by a method similar to that of Example 1g To a solution of methylpyrrolidine-3-carboxylate (3 g, 7.08 mmol) in methanol (200 ml) was added 20% palladium hydroxide (300 mg), and the mixture was stirred overnight at room temperature in a hydrogen atmosphere.
  • methylpyrrolidine-3-carboxylate 3 g, 7.08 mmol
  • methanol 200 ml
  • reaction solution was filtered and washed with methanol. Hot water of about 40 ° C. was added to the filtered product to dissolve the solid matter and filtered. The filtrate was combined with the first filtrate and concentrated to obtain a deprotected product (1.7 g).
  • Neutral buffer prepared from potassium dihydrogen phosphate (13.65 g), disodium hydrogen phosphate dodecahydrate (71.6 g), water (1.5 l)] was added to the reaction solution, and ethyl acetate and heptane were added The mixture was filtered. The filtrate was extracted with ethyl acetate, and the organic layer was dried over sodium sulfate and concentrated. The resulting crude product was purified by column chromatography (silica gel, elution solvent: methanol / ethyl acetate) and combined with the filtrate.
  • Example 5c tert-butyl 4-[(3S, 4R) -3- [2- (tert-butoxy) -2-oxoethyl] -1- ⁇ [2-chloro-6- (trifluoromethyl) phenyl] Methyl ⁇ -4-methylpyrrolidine-3-amide] piperidine-1-carboxylate tert-butyl 4-[(3S, 4R) -3- [2- (tert-butoxy) -2-oxoethyl obtained in Example 5b ]-1-[(2,6-dichlorophenyl) methyl] -4-methylpyrrolidine-3-amide] piperidine-1-carboxylate (758 mg, 1.29 mmol) in methanol (20 ml) in 20% palladium hydroxide ( 75.8 mg) was added, and the mixture was stirred at 40 ° C.
  • Example 5d 2-[(3S, 4R) -1- ⁇ [2-Chloro-6- (trifluoromethyl) phenyl] methyl ⁇ -4-methyl-3-[(piperidin-4-yl) carbamoyl] Pyrrolidin-3-yl] acetic acid tert-butyl 4-[(3S, 4R) -3- [2- (tert-butoxy) -2-oxoethyl] -1- ⁇ [2-chloro-6] obtained in Example 5c
  • piperidine-1-carboxylate 82 mg, 0.133 mmol
  • dichloromethane dehydrated
  • trifluoroacetic acid 3 mL
  • Example 5e 2-[(3S, 4R) -1- ⁇ [2-chloro-6- (trifluoromethyl) phenyl] methyl ⁇ -3- ⁇ [1- (cyclohex-1-ene-1- (Ilmethyl) piperidin-4-yl] carbamoyl ⁇ -4-methylpyrrolidin-3-yl] acetic acid 2-[(3S, 4R) -1- ⁇ [2-chloro-6- ( To a solution of trifluoromethyl) phenyl] methyl ⁇ -4-methyl-3-[(piperidin-4-yl) carbamoyl] pyrrolidin-3-yl] acetic acid (15 mg, 0.0325 mmol) in tetrahydrofuran (dehydrated) (2 mL) Cyclohex-1-ene-1-carbaldehyde (25.9 ⁇ l, 0.227 mmol), acetic acid (30 ⁇ l) and sodium triacetoxyborohydride (68.8 mg, 0.3 25
  • Example 6a (3S, 4R) -3- [2- (tert-butoxy) -2-oxoethyl] -1-[(2-chloro-6-methylphenyl) methyl] -4-methylpyrrolidine-3- Carboxylic acid (3S, 4R) -3- [2- (tert-Butoxy) -2-oxoethyl] -4-methyl obtained by a method similar to that described in Example 1i by a method similar to that described in Example 1j The title compound (154 mg, yield 27.2%) was obtained from pyrrolidine-3-carboxylic acid (360 mg, 1.48 mmol) and 2-chloro-6-methylbenzaldehyde (416 mg, 2.69 mmol).
  • Example 6b tert-butyl 2-[(3S, 4R) -1-[(2-chloro-6-methylphenyl) methyl] -3- ⁇ [1- (cyclohex-1-en-1-ylmethyl) ) Piperidin-4-yl] carbamoyl ⁇ -4-methylpyrrolidin-3-yl] acetate
  • the (3S, 4R) -3- [2- [2] obtained in Example 6a was prepared in a manner similar to that described in Example 1k.
  • Example 6c 2-[(3S, 4R) -1-[(2-chloro-6-methylphenyl) methyl] -3- ⁇ [1- (cyclohex-1-en-1-ylmethyl) piperidine- 4-yl] carbamoyl ⁇ -4-methylpyrrolidin-3-yl] acetic acid
  • tert-butyl 2-[(3S, 4R) -1- obtained in Example 6b [(2-Chloro-6-methylphenyl) methyl] -3- ⁇ [1- (cyclohex-1-en-1-ylmethyl) piperidin-4-yl] carbamoyl ⁇ -4-methylpyrrolidin-3-yl]
  • the title compound (140 mg, yield 73.4%) was obtained from acetate (212 mg, 0.38 mmol).
  • Example 7a Cyclopent-1-ene-1-carbaldehyde
  • 1,2-cyclohexanediol (12 g, 103 mmol) and diethyl ether (150 ml) was mixed with sodium periodate (28.6 g, 134 mmol) and water ( 250 ml) was added and stirred at room temperature for 35 minutes.
  • a 20% aqueous potassium hydroxide solution (40 ml, 206 mmol) was added to the reaction mixture, and the mixture was stirred at room temperature for 2 hours.
  • the reaction mixture was extracted twice with diethyl ether.
  • the organic layer was dried over anhydrous magnesium sulfate and the solvent was distilled off to obtain the title compound (6.1 g, yield 61.6%).
  • Example 7b 2-[(3S, 4R) -1- ⁇ [2-Chloro-6- (trifluoromethyl) phenyl] methyl ⁇ -3- ⁇ [1- (cyclopent-1-en-1-ylmethyl) ) Piperidin-4-yl] carbamoyl ⁇ -4-methylpyrrolidin-3-yl] acetic acid
  • 2-[(3S, 4R) -1- Performed with ⁇ [2-chloro-6- (trifluoromethyl) phenyl] methyl ⁇ -4-methyl-3-[(piperidin-4-yl) carbamoyl] pyrrolidin-3-yl] acetic acid (334 mg, 0.723 mmol) Cyclopent-1-ene-1-carbaldehyde obtained in Example 7a (209 mg, 2.17 mmol), acetic acid (300 ⁇ l) and sodium triacetoxyborohydride (460 mg, 2.1) The title compound from mmol)
  • Example 8 2-[(3S, 4R) -1-[(2-chloro-6-methylphenyl) methyl] -3- ⁇ [(1-cyclopent-1-en-1-ylmethyl) piperidine-4 -Yl] carbamoyl ⁇ -4-methylpyrrolidin-3-yl] acetic acid
  • Example 8a tert-butyl 4-[(3S, 4R) -3-[(2-tert-butoxy) -2-oxoethyl] -1-[(2-chloro-6-methylphenyl) methyl] -4 -Methylpyrrolidine-3-amido ⁇ piperidine-1-carboxylate Obtained (3S, 4R) -3-[(2) in a manner similar to that described in Example 6a by a method similar to that described in Example 1k.
  • Example 8b 2-[(3S, 4R) -1-[(2-chloro-6-methylphenyl) methyl] -3- ⁇ [(1-cyclopent-1-en-1-ylmethyl) piperidine-4 -Yl] carbamoyl ⁇ -4-methylpyrrolidin-3-yl] acetic acid tert-butyl 4-[(3S, 4R) -3-[(2-tert-butoxy) -2-oxoethyl]-obtained in Example 8a 1-[(2-chloro-6-methylphenyl) methyl] -4-methylpyrrolidine-3-amide ⁇ piperidine-1-carboxylate (237 mg, 0.42 mmol), trifluoroacetic acid (2.3 ml, 31 mmol), And a mixture of dichloromethane (dehydrated) (2.3 ml) was stirred at room temperature for 3 hours 30 minutes.
  • Example 9a tert-Butyl N-[(3S) -1- (cyclohex-1-en-1-ylmethyl) pyrrolidin-3-yl] carbamate (3S)-( ⁇ )-3- (tert-butoxy Carbonylamino) pyrrolidine (2.0 g, 10.8 mmol), acetic acid (1.24 ml, 21.6 mmol) and tetrahydrofuran (dehydrated) (27 ml) were mixed with 1-cyclohexene-1-carboxaldehyde (1.48 ml, 13 mmol).
  • Example 9b (3S) -1- (Cyclohex-1-en-1-ylmethyl) pyrrolidin-3-amine tert-butyl N-[(3S) -1- (cyclohex-- obtained in Example 9a
  • Example 9c tert-butyl 2-[(3S, 4R) -3- ⁇ [(3S) -1- (cyclohex-1-en-1-ylmethyl) pyrrolidin-3-yl] carbamoyl ⁇ -1- [(2,6-Dichlorophenyl) methyl] -4-methylpyrrolidin-3-yl] acetate (3S) -1- (cyclohex-) obtained in Example 9b by a method similar to that described in Example 1k 1-en-1-ylmethyl) pyrrolidin-3-amine (169 mg, 0.94 mmol) and (3S, 4R) -3- [2- (tert-butoxy) -2-oxoethyl]-obtained in Example 2k The title compound (236 mg, 58% yield) was obtained from 1-[(2,6-dichlorophenyl) methyl] -4-methylpyrrolidine-3-carboxylic acid (290 mg, 0.72 mmol).
  • Example 9d 2-[(3S, 4R) -3- ⁇ [(3S) -1- (Cyclohex-1-en-1-ylmethyl) pyrrolidin-3-yl] carbamoyl ⁇ -1-[(2 , 6-Dichlorophenyl) methyl] -4-methylpyrrolidin-3-yl] acetic acid
  • the title compound (173 mg, 81% yield) was obtained from -yl] acetate (236 mg, 0.42 mmol).
  • Example 10a 1-Hexylpiperidin-4-amine The title compound was obtained in a manner similar to that described in US2005 / 0222175 A1 and Examples 4a and 4b.
  • Example 10b Methyl 3-chloro-2-methylbenzoate 3-chloro-2-methylbenzoic acid (3.58 g, 21 mmol), potassium carbonate (5.8 g, 42 mmol), N, N-dimethylformamide (35. 9 ml) was added with iodomethane (1.96 ml, 31.5 mmol) and stirred at room temperature for 18 hours 30 minutes. Water and ethyl acetate were added to the reaction solution to extract the organic layer. The organic layer was washed successively with saturated aqueous ammonium chloride solution and saturated brine, dried over sodium sulfate, filtered and concentrated.
  • Example 10d [2- (Bromomethyl) -3-chlorophenyl] methanol
  • Dichloromethane (10 ml) was added to methyl 2- (bromomethyl) -3-chlorobenzoate (500 mg, 1.9 mmol) obtained in Example 10c to -78.
  • a 1.04 M diisobutylaluminum hydride / n-hexane solution (4.57 ml, 4.75 mmol) was added, and the mixture was stirred under a nitrogen atmosphere for 1 hour.
  • a saturated aqueous Rochelle salt solution and tert-butyl methyl ether were added, and the mixture was extracted with tert-butyl methyl ether.
  • Example 10f 2- (Bromomethyl) -1-chloro-3- (difluoromethyl) benzene 2- (Bromomethyl) -3-chlorobenzaldehyde (289 mg, 1.24 mmol) obtained in Example 10e was added to dichloromethane (10 ml). Then, [bis (2-methoxyethyl) amino] sulfur trifluoride (457 ⁇ l, 2.48 mmol) was added at 0 ° C., and the mixture was stirred at room temperature for 1.5 hours under a nitrogen atmosphere. Saturated aqueous sodium hydrogen carbonate solution was added to the reaction mixture at 0 ° C., and the mixture was extracted with diethyl ether.
  • Example 10g (3RS, 4SR) -3- [2- (tert-butoxy) -2-oxoethyl] -1-[(2,6-dichlorophenyl) methyl] -4-methylpyrrolidine-3-carboxylic acid
  • Benzyl (3RS, 4SR) -1-benzyl-3- [2- (tert-butoxy) -2-oxoethyl] -4-methylpyrrolidine-3-carboxylate (8.35 g, obtained in a similar manner as Example 1g
  • Neutral buffer prepared from potassium dihydrogen phosphate (13.65 g), disodium hydrogen phosphate dodecahydrate (71.6 g), water (1.5 L)] and ethyl acetate were added to the reaction mixture, and the solid was added. Filtered. The solid on the filter paper was washed with ethyl acetate to give the title compound as a white solid. The filtrate was extracted with ethyl acetate, and the organic layer was dried over sodium sulfate, concentrated and purified by column chromatography (silica gel, elution solvent: methanol / ethyl acetate). 3.77 g, yield 58.2%).
  • Example 10h tert-butyl 2-[(3S, 4R) -1-[(2,6-dichlorophenyl) methyl] -3-[(1-hexylpiperidin-4-yl) carbamoyl] -4-methylpyrrolidine -3-yl] acetate (3RS, 4SR) -3- [2- (tert-butoxy) -2-oxoethyl] -1-[(2,6-dichlorophenyl) methyl] -4-methyl obtained in 10 g of Example 1-hexylpiperidin-4-amine (894 mg, 4.85 mmol) obtained in Example 10a, triethylamine (1.04 ml, 7.46 mmol), N in pyrrolidine-3-carboxylic acid (1.5 g, 3.73 mmol) , N-dimethylformamide (10 ml) and PyBOP (2.52 g, 4.85 mmol) were added and stirred overnight at room temperature.
  • Example 10i tert-Butyl 2-[(3S, 4R) -3-[(1-hexylpiperidin-4-yl) carbamoyl] -4-methylpyrrolidin-3-yl] acetate
  • the tert obtained in Example 10h -Butyl 2-[(3S, 4R) -1-[(2,6-dichlorophenyl) methyl] -3-[(1-hexylpiperidin-4-yl) carbamoyl] -4-methylpyrrolidin-3-yl] acetate
  • Methanol (10 ml) and 20% palladium hydroxide (50 mg) were added to 250 mg of the solution, and the mixture was stirred at room temperature for 2 hours in a hydrogen atmosphere.
  • Example 10j tert-butyl 2-[(3S, 4R) -1- ⁇ [2-chloro-6- (difluoromethyl) phenyl] methyl ⁇ -3-[(1-hexylpiperidin-4-yl) carbamoyl ] -4-Methylpyrrolidin-3-yl] acetate
  • Example 10k 2-[(3S, 4R) -1- ⁇ [2-chloro-6- (difluoromethyl) phenyl] methyl ⁇ -3-[(1-hexylpiperidin-4-yl) carbamoyl] -4 -Methylpyrrolidin-3-yl] acetic acid
  • Example 11a (3S, 4R) -3- [2- (tert-butoxy) -2-oxoethyl] -1-[(2,6-dichlorophenyl) methyl] -4-methylpyrrolidine-3-carboxylic acid (3S, 4R) -3- [2- (tert-Butoxy) -2-oxoethyl] -4-methylpyrrolidine-3-carboxylic acid (300 mg, 1.23 mmol) obtained in the same manner as in Example 1i with methanol ( 3 ml), 2,6-dichlorobenzaldehyde (431 mg, 2.46 mmol), acetic acid (73.8 ul, 1.23 mmol) and sodium triacetoxyborohydride (521 mg, 2.46 mmol) were added and stirred at room temperature for 2 days.
  • Example 11b tert-butyl 2-[(3S, 4R)- ⁇ 3-[(1-cyclohex-1-en-1-ylmethyl) piperidin-4-yl] carbamoyl-1-[(2,6 -Dichlorophenyl) methyl] -4-methylpyrrolidin-3-yl ⁇ acetate (3S, 4R) -3- [2- (tert-butoxy) obtained in Example 11a by a method similar to that described in Example 1k.
  • Example 11c 2-[(3S, 4R) -3- ⁇ [(1-Cyclohex-1-en-1-ylmethyl) piperidin-4-yl] carbamoyl ⁇ -1-[(2,6-dichlorophenyl ) Methyl] -4-methylpyrrolidin-3-yl] acetic acid
  • To give the title compound (169 mg, yield 68.2%).
  • Example 12 2-[(3S, 4R) -1- ⁇ [2-Chloro-6- (difluoromethyl) phenyl] methyl ⁇ -3- ⁇ [1- (cyclohex-1-en-1-ylmethyl) ) Piperidin-4-yl] carbamoyl ⁇ -4-methylpyrrolidin-3-yl] acetic acid
  • Example 12a tert-Butyl 4-[(3S, 4R) -3- [2- (tert-butoxy) -2-oxoethyl] -1- ⁇ [2-chloro-6- (difluoromethyl) phenyl] methyl ⁇ -4-Methylpyrrolidine-3-amide] piperidine-1-carboxylate tert-butyl 4-[(3S, 4R) -3- [2- (tert-butoxy) -2-oxoethyl] obtained in Example 3b -4-Methylpyrrolidine-3-amide] piperidine-1-carboxylate (375 mg, 0.881 mmol) was dissolved in N, N-dimethylformamide (7 ml).
  • Example 12b 2-[(3S, 4R) -1- ⁇ [2-Chloro-6- (difluoromethyl) phenyl] methyl ⁇ -3- ⁇ [1- (cyclohex-1-en-1-ylmethyl) ) Piperidin-4-yl] carbamoyl ⁇ -4-methylpyrrolidin-3-yl] acetic acid tert-butyl 4-[(3S, 4R) -3- [2- (tert-butoxy) -2 obtained in Example 12a -Oxoethyl] -1- ⁇ [2-chloro-6- (difluoromethyl) phenyl] methyl ⁇ -4-methylpyrrolidine-3-amido] piperidine-1-carboxylate (332 mg, 0.553 mmol) was added to dichloromethane (3.
  • Example 13 2-[(3S, 4R) -1- ⁇ [2-Chloro-6- (difluoromethyl) phenyl] methyl ⁇ -3- ⁇ [1- (cyclopent-1-en-1-ylmethyl) Piperidin-4-yl] carbamoyl ⁇ -4-methylpyrrolidin-3-yl] acetic acid
  • the intermediate (186 mg) obtained in Example 12b and the cyclopent-1-ene-1-carbaldehyde obtained in Example 7a ( 79.9 mg, 0.831 mmol) and the title compound (76 mg) was obtained in the same manner as described for 12b.
  • Example 14a 1- (Cyclohexylmethyl) piperidin-4-amine The title compound was obtained in a manner similar to that described in US2005 / 0222175 A1 and Examples 4a and 4b.
  • Example 14b tert-butyl 2-[(3S, 4R) -1-benzyl-3- ⁇ [1- (cyclohexylmethyl) piperidin-4-yl] carbamoyl ⁇ -4-methylpyrrolidin-3-yl] acetate (3S, 4R) -1-benzyl-3- [2- (tert-butoxy) -2-oxoethyl] -4-methylpyrrolidine- obtained in Example 1j by a method similar to that described in Example 1k The title compound (250 mg, yield: 81.4%) was obtained from 3-carboxylic acid (200 mg, 0.6 mmol) and 1- (cyclohexylmethyl) piperidin-4-amine (141 mg, 0.72 mmol) obtained in Example 14a.
  • Example 14c tert-butyl 2-[(3S, 4R) -1- ⁇ [2-chloro-6- (difluoromethyl) phenyl] methyl ⁇ -3- ⁇ [1- (cyclohexylmethyl) piperidine-4- Yl] carbamoyl ⁇ -4-methylpyrrolidin-3-yl] acetate
  • tert-butyl 2-[(3S, 4R) -1-benzyl- obtained in Example 14b 3- ⁇ [1- (Cyclohexylmethyl) piperidin-4-yl] carbamoyl ⁇ -4-methylpyrrolidin-3-yl] acetate (250 mg, 0.489 mmol) was obtained in the same manner as in Example 10f.
  • Example 14d 2-[(3S, 4R) -1- ⁇ [2-Chloro-6- (difluoromethyl) phenyl] methyl ⁇ -3- ⁇ [1- (cyclohexylmethyl) piperidin-4-yl] carbamoyl ⁇ -4-Methylpyrrolidin-3-yl] acetic acid
  • benzyl chloroformate (6.35 ml, 44.5 mmol) and 2N aqueous sodium hydroxide solution (22.3 ml) were simultaneously added with ice-cooling and stirring (0-1 ° C.) at an internal temperature of 3.5 ° C. or less. It was added dropwise over 20 minutes.
  • the reaction solution was stirred in an ice bath and gradually returned to room temperature.
  • the mixture was stirred at room temperature overnight.
  • the reaction solution was adjusted to pH 12 by adding 1N aqueous sodium hydroxide solution (10 ml) under ice-cooling and stirring (internal temperature around 15 ° C.). The reaction solution was returned to room temperature and washed three times by adding ethyl ether.
  • the aqueous layer was adjusted to pH 2-3 by successively adding 2N aqueous hydrochloric acid (20.2 ml) and 1N aqueous hydrochloric acid (13 ml) under ice-cooling and stirring (internal temperature of 5 ° C. or less).
  • the aqueous layer was returned to room temperature and extracted three times with ethyl acetate.
  • the organic layer was washed with saturated brine, dried over sodium sulfate, filtered and concentrated.
  • the residue was dissolved in ethyl acetate, washed 4 times with water and then with saturated brine, dried over sodium sulfate, filtered and concentrated to give the title compound (14.53 g, yield: 95.1%). It was.
  • Oxoethyl] -4-methylpyrrolidine-3-carboxylic acid 500 mg
  • hydrogen phosphate (R)-( ⁇ )-1,1′-binaphthyl-2,2′-diyl 359 mg
  • ethanol 10.0 mL
  • water 10.0 mL
  • the precipitated solid was collected by filtration and washed with a 1: 1 ethanol-water mixture (2 mL).
  • the wet substance was dried under reduced pressure at 40 ° C. for about 1 hour to obtain the title compound (269 mg, yield: 20.5%).
  • Example Compounds 1 to 8 are as follows.
  • Example Compounds 9 to 14 are as follows.
  • T cell transfer colitis model (Test Example 2) Body weight decrease inhibitory effect in T cell transfer colitis model (1) Method Using a colitis model induced by transferring CD4 positive CD45RB high positive cells collected from BALB / c mice into SCID mice, The body weight reduction inhibitory effect of the example compounds was examined. The experiment was carried out for 31 days. On the first day, CD4 positive CD45RB high positive cells (5 ⁇ 10 5 cells / mouse) collected from the spleen of Balb / c mice were intravenously administered to SCID mice. From the 16th day to the 31st day, the Example compounds were orally administered to SCID mice once a day, and body weights were measured on the 19th, 22nd, 24th, 26th, 29th and 31st days.
  • the body weight reduction inhibitory effect was evaluated by the body weight change rate (%) on the 19th, 22nd, 24th, 26th, 29th and 31st days.
  • the body weight on the 16th day is [A]
  • the body weight on each body weight measurement day is [B].
  • the rate (%) was determined.
  • Body weight change rate (%) B / A ⁇ 100

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ES12831085.1T ES2564732T3 (es) 2011-09-13 2012-09-11 Derivado de ácido pirrolidin-3-ilacético
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CA2844617A CA2844617C (en) 2011-09-13 2012-09-11 Pyrrolidine-3-ylacetic acid derivative
MX2014002210A MX358494B (es) 2011-09-13 2012-09-11 Derivado de acido pirrolidin-3-ilacetico.
DK12831085.1T DK2757103T3 (en) 2011-09-13 2012-09-11 Pyrrolidin-3-yl-acetic acid derivative
SI201230463T SI2757103T1 (sl) 2011-09-13 2012-09-11 Derivati pirolidin-3-ilocetne kisline
MEP-2016-37A ME02383B (me) 2011-09-13 2012-09-11 Derivat pirolidin-3-ilsirćetne kiseline
SG11201400163WA SG11201400163WA (en) 2011-09-13 2012-09-11 Pyrrolidine-3-ylacetic acid derivative
RU2014107536A RU2615135C2 (ru) 2011-09-13 2012-09-11 Производное пирролидин-3-илуксусной кислоты
RS20160106A RS54582B1 (en) 2011-09-13 2012-09-11 PYROLIDINE-3-ILSIRCETIC ACID DERIVATIVE
NZ620469A NZ620469B2 (en) 2011-09-13 2012-09-11 Pyrrolidine-3-ylacetic acid derivative
EP12831085.1A EP2757103B1 (en) 2011-09-13 2012-09-11 Pyrrolidine-3-ylacetic acid derivative
CN201280041634.0A CN103764648B (zh) 2011-09-13 2012-09-11 吡咯烷-3-基乙酸衍生物
PL12831085T PL2757103T3 (pl) 2011-09-13 2012-09-11 Pochodna kwasu pirolidyn-3-ylooctowego
AU2012309556A AU2012309556B2 (en) 2011-09-13 2012-09-11 Pyrrolidine-3-ylacetic acid derivative
BR112014004267-5A BR112014004267B1 (pt) 2011-09-13 2012-09-11 Derivado de ácido pirrolidina-3-ilacético
UAA201401661A UA112873C2 (uk) 2011-09-13 2012-11-09 Похідна піролідин-3-ілоцтової кислоти
IL230804A IL230804A (en) 2011-09-13 2014-02-03 Annals of pyrrolidine-3-acetic acid ram and medical components for the treatment of inflammatory bowel disease
ZA2014/00918A ZA201400918B (en) 2011-09-13 2014-02-06 Pyrrolidine-3-ylacetic acid derivative
HK14106800.1A HK1193407A1 (en) 2011-09-13 2014-07-04 Pyrrolidine-3-ylacetic acid derivative -3-
HRP20160166TT HRP20160166T1 (hr) 2011-09-13 2016-02-16 Derivat pirolidin-3-iloctene kiseline
SM201600071T SMT201600071B (it) 2011-09-13 2016-03-10 Derivato di acido pirrolidina-3-ilacetico

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WO2014142056A1 (ja) * 2013-03-12 2014-09-18 エーザイ・アール・アンド・ディー・マネジメント株式会社 ピロリジン－３－イル酢酸誘導体の塩およびその結晶
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WO2014142056A1 (ja) * 2013-03-12 2014-09-18 エーザイ・アール・アンド・ディー・マネジメント株式会社 ピロリジン－３－イル酢酸誘導体の塩およびその結晶
JP5872105B2 (ja) * 2013-03-12 2016-03-01 エーザイ・アール・アンド・ディー・マネジメント株式会社 ピロリジン−３−イル酢酸誘導体の塩およびその結晶
US9550732B2 (en) 2013-03-12 2017-01-24 Eisai R&D Management Co., Ltd. Salt of pyrrolidin-3-yl acetic acid derivative and crystals thereof
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WO2014142086A1 (ja) * 2013-03-13 2014-09-18 エーザイ・アール・アンド・ディー・マネジメント株式会社 ピロリジン－３－イル酢酸誘導体およびピペリジン－３－イル酢酸誘導体
WO2024083933A1 (en) 2022-10-19 2024-04-25 Astrazeneca Ab 2,4,6-trisubstituted 1,3,5-triazines as modulators of cx 3cr1

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MX358494B (es) 2018-08-23
TW201311667A (zh) 2013-03-16
HUE026824T2 (en) 2016-07-28
PL2757103T3 (pl) 2016-06-30
SI2757103T1 (sl) 2016-04-29
JPWO2013039057A1 (ja) 2015-03-26
CN103764648B (zh) 2015-07-01
CL2014000484A1 (es) 2014-08-22
BR112014004267B1 (pt) 2021-11-16
RU2615135C2 (ru) 2017-04-04
PE20141353A1 (es) 2014-09-26
EP2757103B1 (en) 2016-01-06
DK2757103T3 (en) 2016-03-07
CN103764648A (zh) 2014-04-30
CA2844617A1 (en) 2013-03-21
SG11201400163WA (en) 2014-06-27
IL230804A0 (en) 2014-03-31
CA2844617C (en) 2019-03-05
IL230804A (en) 2016-02-29
KR20140060286A (ko) 2014-05-19
RS54582B1 (en) 2016-08-31
SMT201600071B (it) 2016-04-29
KR101963922B1 (ko) 2019-03-29
MX2014002210A (es) 2014-04-30
CY1117460T1 (el) 2017-04-26
AU2012309556B2 (en) 2016-09-15
ES2564732T3 (es) 2016-03-28
EP2757103A4 (en) 2015-02-18
AR087788A1 (es) 2014-04-16
PT2757103E (pt) 2016-03-31
BR112014004267A2 (pt) 2017-03-21
JO3082B1 (ar) 2017-03-15
MY169869A (en) 2019-05-27
UA112873C2 (uk) 2016-11-10
RU2014107536A (ru) 2015-10-20
EP2757103A1 (en) 2014-07-23
HK1193407A1 (en) 2014-09-19
NZ620469A (en) 2015-06-26
TWI543975B (zh) 2016-08-01
HRP20160166T1 (hr) 2016-03-11
ME02383B (me) 2016-06-20
AU2012309556A1 (en) 2014-02-27
JP5829689B2 (ja) 2015-12-09

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